With time ticking away, clinicians scramble to save newborn twins from the disease that took their brother

A decade earlier, her happy, easygoing little boy had died just after his second birthday. And now here she was, pregnant with twin boys, hoping against hope that they wouldn’t have the same mutated gene that killed their older brother. So when Alyssa Martin found out 21 weeks into her pregnancy that they, too, had inherited the faulty DNA, “it just felt like the end of the world,” she said.

This time, though, Martin knew what she was up against. While she was still pregnant, she and a team of doctors devised a plan to try to save the twins. The boys’ best hope was an experimental drug — a form of copper injected under the skin twice a day — designed to counteract the effects of that mutated gene, which wreaks such havoc on the body’s copper levels that it often kills boys before age 3. If the medication was to have a chance of working, doctors believed, it was crucial that the twins get it within weeks after birth — so time was of the essence.

But getting that drug to Charlie and Kolton Martin proved to be harder than anyone imagined.

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In the weeks after the twins were born in December, a University of Iowa medical geneticist and her team went to extraordinary lengths as they raced to obtain the medication. Again and again, they were forced to improvise as they encountered unforeseen obstacles: They were stuck in limbo during a weeks-long period in which both a drug company and representatives from the National Institutes of Health said they were powerless to help. The twins developed painful welts and then a worrisome respiratory infection.

And during the polar vortex that chilled the Midwest last week, when a courier company hired to transport the drug across Iowa took its drivers off the road, a research assistant drove through a frigid blur of swirling snow to pick up the medication at the airport.

The saga highlights the dedication of the clinicians who scrambled to help. But it also shows how confusing it can be to try to access experimental drugs for patients like Charlie and Kolton who have little in the way of time and options.

STAT interviewed the key players to piece together this account, which is recounted in detail here for the first time.

The twins and their late older brother, Dylan Martin, had inherited a rare neurodegenerative disorder called Menkes disease. It’s thought to affect 1 in 100,000 newborns, almost always boys. Menkes babies often appear normal until a few months after birth, when their disease manifests in devastating ways: Their growth slows. They miss milestones. They are intellectually disabled. And distinctively, they have brittle, colorless hair.

Menkes is caused by mutations in a gene on the X chromosome known as ATP7A, which is involved in making sure that the copper in the food you eat gets properly distributed into different parts of the body — a process that’s vital for function and development. The more severe a Menkes boy’s mutations, the more severe his disease and the less responsive it’s believed to be to treatment.

There is no Menkes treatment approved by the Food and Drug Administration. It is a disease with so little recourse that one foundation for Menkes boys says the best way to treat it is with “love, lots of cuddles, and quality time.”

But for decades, clinicians have been experimenting with giving Menkes boys copper replacement treatments, encouraged by signs that some who get it injected under their skin seem to do better.

In a study published in 2014, researchers at the NIH followed two groups of Menkes patients. The first group of 35 patients started getting daily injections of a copper replacement treatment known as copper histidine before they turned 1 month old. The second group of 22 boys started dosing later, after symptoms had emerged.

By age 3, 71 percent of patients in the early-treatment group were still alive; that group improved in their movement abilities, their personal and social development, their language skills, and their head size. But in the later-treatment group, just half of the boys were still alive by age 3.

The data were promising enough to inspire New York-based Cyprium Therapeutics, a subsidiary of a drug company called Fortress Biotech, to license the drug from the NIH in 2017. The company hopes at some point in the future to use newer data to seek FDA approval to market the drug for Menkes; the drug has also been tested in mice to see if it could be paired with gene therapy that would parachute in a functional gene to replace the faulty DNA.

But the 2014 study also offers a sobering takeaway: To have a shot at working, copper histidine needs to be given early. And even then it still might not work.

Dylan MartinCourtesy Alyssa Martin

Alyssa Martin, 36, is a single mom and an inspector in a factory that makes drill bits. For most of her life, she’s lived in Davenport, a community on the eastern border of Iowa that sits along the Mississippi River. She has a determined calmness about her, a quiet strength born of weathering a parent’s nightmare.

When Martin gave birth to Dylan in 2005, he seemed like a normal newborn. But then at 3 months old, he started having seizures. Testing revealed that Martin was a healthy carrier of Menkes, and that Dylan had inherited it. There was no warning: Martin is adopted, and she tracked down her biological parents, who have no family history of the disease.

Dylan started copper histidine treatment when he was 4 months old. It was, of course, not commercially available then, either, but Martin doesn’t recall the pathway by which Dylan accessed the drug.

Whether it was because he started it too late, or because his mutations were too severe, or because of some other unknowable reason, the drug didn’t work for Dylan.

Dylan stopped eating when he was 6 months old. His bones turned brittle. He was never able to crawl. To breathe, he had to be hooked up to oxygen. He died when he was 25 months old. Martin buried him in a cemetery not far from where she lives now in Davenport.

“Losing him was very, very hard,” she said.

Martin grieved and picked herself back up. In 2014, she learned she was expecting a baby girl. The news came as a relief, since girls are almost always protected against X-linked genetic disorders like Menkes because they have two X chromosomes. Martin’s daughter, Natalie, is now a healthy 4-year-old.

Then, last year, came the news that Martin was pregnant, this time with twin boys. Martin was at home when she got the call from a genetic consultant: Prenatal testing showed that both boys had Menkes.

Martin sought care about an hour’s drive away from her home at the University of Iowa Stead Family Children’s Hospital, where she met the medical geneticist who would become her sons’ champion: Dr. Amy Calhoun.

Before taking on their case, Calhoun had never before personally managed a case of Menkes, nor had she managed to convince a company to let a patient access an experimental drug outside of a clinical trial. But in some ways the case was right up her alley: Calhoun has been practicing for seven years, as something of a medical detective devoted to figuring out how to treat rare inherited diseases that most physicians only read about. Upbeat and friendly, Calhoun speaks with a Midwestern accent (she was born and educated in Iowa) and fondly refers to the Martin twins as “the guys.”

The guys came into the world early, on Dec. 17, when Martin was 33 weeks into her pregnancy. Charlie came first, at 4 pounds, 5 ounces. Kolton followed him six minutes later, at 4 pounds, 12 ounces.

The twins, who are fraternal, cry with a different tenor, and they already have distinctive looks: Charlie has hair. Kolton is bald, with “old-man wrinkles” on his forehead, as Martin affectionately puts it.

Because they were born prematurely (common with Menkes boys), the twins had to spend their first weeks in the neonatal intensive care unit. Their early birth also affected plans for treating their Menkes: Their kidneys were still too underdeveloped for them to get copper replacement treatment as early as would be recommended for full-term Menkes babies, so Calhoun would have a few weeks of wiggle room to obtain the copper histidine.

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The day after the twins were born, Calhoun got on the phone with Dr. Stephen Kaler, the NIH researcher who led the 2014 study suggesting that early copper histidine treatment benefits some Menkes patients. Kaler was now wrapping up another study examining whether Menkes patients who receive copper histidine live longer compared to those who do not receive injections.

That study was closed and its data being analyzed, so the twins wouldn’t be able to enroll and get the drug that way.

Instead, they would have to try to get the drug through the FDA’s expanded access program. It’s the pathway that critics of the controversial new federal “right to try” law point to favorably as an established and reliable route for patients to get drugs that aren’t yet approved. As part of the process of submitting an expanded-access application to the FDA, a clinician like Calhoun must first persuade the experimental drug’s manufacturer to agree to supply it. She must also convince the ethics review board of her home institution to sign off on what is essentially a tiny clinical trial. When the boxes are checked, and the situation is appropriate, the FDA usually grants approval quickly.

With Kaler’s guidance, Calhoun spent the holidays racing to complete the paperwork. On the day after Christmas, while her husband took their children to visit her parents, Calhoun was in her office working on the twins’ case. Right after New Year’s Day, she wrote a 10-page research protocol and a five-page consent form, both from scratch, so that her institution’s ethics board could do a quick review.

The process stalled, however, when it came to getting a guarantee that the drug could be supplied.

Calhoun and her team had been under the impression that their efforts to obtain the drug were delayed in part by the record-long shutdown of the federal government, which stretched from Dec. 22 until Jan. 25. But the NIH and the FDA both said their relevant operations were running normally during that period.

Instead, the main holdup seemed to involve a technicality in who was the legal holder of the investigational new drug application under which the FDA was allowing the treatment to be tested in clinical trials.

Around the time of the twins’ birth, the IND for copper histidine was in the process of being transferred from NIH to Cyprium. The NIH filed its transfer paperwork with the FDA just two days after the twins were born, according to documents and correspondences that STAT obtained via a public records request. The NIH was at that point “no longer involved” with the IND transfer, the agency said. Cyprium, meanwhile, maintains that negotiations over the IND transfer continued until Jan. 14, before which it couldn’t file its own transfer paperwork and was therefore legally powerless to help the twins, as much as it wanted to do so.

Either way, “it was in this weird limbo,” said Sam Marcellus, a research assistant who works on clinical trials at the University of Iowa’s hospital and dedicated weeks to aiding Calhoun on the case.

As the days ticked by without forward progress, Calhoun and Marcellus tried everything they could think of: They went through backchannels. They sought help, unsuccessfully, from the office of one of their local lawmakers, Republican Sen. Chuck Grassley.

Still, the waiting dragged on. A few days into January, when the twins were 18 days old, Calhoun decided they shouldn’t wait any longer to get their copper levels up.

She started them on injections of copper chloride, another copper replacement therapy, four times a day. Copper chloride is FDA-approved as a supplemental nutrient delivered directly into the veins, but it comes with a serious side effect: In almost all cases, it eventually causes irritating welts that can look like Hot Tamales cinnamon candies. (That’s why clinicians who work with Menkes boys prefer to try copper histidine, even though it’s not FDA-approved and must typically be obtained through a clinical trial or the FDA’s expanded access program.)

The twins were released from the NICU on Jan. 13, at almost a month old. For the first time, Martin could take them home, where they were greeted with sparkling new things but also a few cherished hand-me-down blankets, baby mobiles, and clothing from Dylan.

Martin continued to give the twins their copper chloride injections, but sure enough, after a couple weeks large blisters bloomed on their skin. Charlie, in particular, had a notably bad reaction. Calhoun gave Martin the OK to stop giving the boys the irritating treatment on Jan. 22.

Calhoun felt comfortable pausing treatment because there’d just been a procedural breakthrough: The IND had finally been transferred from the NIH to Cyprium, which meant that Cyprium said it could finally agree to supply the drug — and Calhoun could finally submit the boys’ expanded-access application to the FDA. That same day, Calhoun’s team stuffed the application in a FedEx package and mailed it at overnight delivery speed to the FDA — setting in motion all the normal wheels to get it quickly approved.

But as those wheels were turning, another setback emerged on Jan. 25: Martin noticed that the twins were coughing and having trouble breathing; they also had an unusually low temperature. They had respiratory syncytial virus, or RSV. It’s a common infection that usually looks like a cold, but it can be serious in babies and the elderly. (Having Menkes may have made the twins more susceptible.) They were quickly readmitted to the hospital at the University of Iowa and hooked up to machines to help them breathe.

The FDA said yes, and so did the hospital’s ethics board. And so with all the procedural boxes finally checked, Charlie and Kolton’s copper histidine made its maiden voyage.

Cyprium, which is providing the treatment to the twins for free, sent the box of vials to Iowa on an airplane from the Los Angeles area, where the company pays a contract manufacturer to actually make the product. At 11 p.m. on Jan. 28, the medication landed in Cedar Rapids, Iowa, which at a 40-minute drive away is the closest airport to the University of Iowa’s hospital. A courier was scheduled to transport the box so that it would arrive at the hospital at 9 a.m. the next morning.

But the next morning came and went, with no delivery. Where was the drug?

A call revealed that the courier had taken its drivers off the road because of the polar vortex that was sending temperatures across the region plummeting well below 0 degrees Fahrenheit. The medication was stuck at the airport — and the courier was now saying it couldn’t be transported for another two days.

Marcellus, the research assistant working with Calhoun on the case, volunteered to pick it up instead. That afternoon, she got in her Dodge Charger and sped out to the airport, where the wind chill neared -30 degrees F. Her car windows fogged up and grew with ice; at one point, she said, the wind was blowing the snow so hard around her car she could barely see.

At the airport, Marcellus was directed first to the baggage claim (it wasn’t there) and then to the American Airlines check-in desk (it wasn’t there, either). She finally found the 50-pound box, packed with dry ice, sitting by the refrigerator in the break room for American Airlines staffers. Marcellus drove back to the hospital and hand-delivered the box to the inpatient pharmacist.

But then came yet another setback: When a pharmacist opened the package, a paper thermometer, like the kind used to monitor fish tanks, bore concerning news: Because of the polar vortex, the temperature inside the box had dropped to -23 degrees F, outside the appropriate range of between -10 and -20 degrees F. Calhoun’s team confronted a dread-inducing question: Was the drug ruined?

After a stressful few minutes of uncertainty, Calhoun’s team got the assurance from Kaler. It was still OK to administer.

It would be another two days before Charlie and Kolton would be healthy enough to go home. It will be months before there will be signs of whether the experimental medicine might be working, of whether the twins can sit and move around unassisted. And it may be years before Martin will know whether her sons can have the normal life she so fervently wants for them. But last Tuesday night, as she watched a clinician inject copper histidine under her sons’ skin for the first time, Martin finally allowed herself to feel relieved.

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I think you are confounding individual vs. population analysis. For an Ashkenazi Jew, randomly selected from the population, the probability of being a carrier for the Tay-Sachs allele is about 1 out of 30. In contrast, for a known carrier of Tay-Sachs, the probability for that particular individual to be a carrier is, by definition, 100%.

To Norm: The odds were not 1:100,000. The odds of having a boy is roughly 50-50. Alyssa is a carrier of an X-linked disease. Therefore, the odds of a boy inheriting the disease-causing mutation from her are also 50-50. Two coin flips.